Uric acid is the end product of purine bodies in human. The upper limit of normal uric acid concentration solved in plasma is 7.0 mg/dL independently from sex and age, and the condition with higher concentration is clinically defined as hyperuricemia. Hyperuricemia affects mostly in adult men and is considered to result from combination of a genetic factors involved in metabolism of purine bodies and secondary factors such as consumption of a high-energy food, nucleic acid rich food or the like. Conditions of persistent hyperuricemic increase a risk of developing arthritis following to urate crystal deposition in intra- or peri-joints. The condition with such developed arthritis is called gout, and the arthritis is called gouty attack. Hyperuricemia is classified broadly into types consisting of a uric acid overproduction-type wherein the uric acid production increases, a uric acid underexcretion-type wherein the uric acid excretion in urine decreases, and a mixed type of them (for example, see Guideline for the management of hyperuricemia and gout, Version 1, 2002 (hereinafter referred to as the Management guideline), pp. 12-22; and Diagnosis and Treatment, Vol. 90, No. 2, pp. 186-191, 2002).
In the prevention or treatment of hyperuricemia or gout, the basis is to control the plasma uric acid level under a certain level to prevent the incidence of gouty arthritis, and the incidence of the gouty arthritis is considered the lowest in the case to control plasma uric acid level within the range from 4.4 to 6.6 mg/dL. So far, for the treatment of hyperuricemia or gout, allopurinol of a uric acid synthesis inhibitor or probenecid, bucolome, benzbromarone of uricosuric drugs or the like have been used for the improvement of the plasma uric acid level. In addition, in the treatment of gouty attacks, an agent for the pain attack such as colchicine, a nonsteroidal anti-inflammatory agent such as indometacin, naproxen, fenbufen, pranoprofen, oxaprozin, and an adrenocortical steroid are used (for example, see the above Management guideline, pp. 23-45).
Allopurinol of a uric acid synthesis inhibitor has side effects such as poisoning syndrome (hypersensitivity angiitis), Stevens-Johnson syndrome, exfoliative dermatitis, aplastic anemia, hepatic insufficiency or the like. In addition, a uricosuric drug has a restriction not to be used for a patient with renal failure, and probenecid, bucolome and benzbromarone have side effects such as gastrointestinal disorder, urinary lithiasis, especially, benzbromarone sometimes causes fulminant hepatic failure in a patient with idiosyncrasy (for example, see the above Management guideline, pp. 32-33).
It has been desired to develop a new preventative or therapeutic drug having few side effects which can solve such problems of these existing drugs, especially with a different mechanism compared with existing drugs from the viewpoint of broadening the choices of treatment methods.
Since hyperuricemia is brought on by life style such as overeating, food preference for high purine, high fat or high protein, habitual drinking, insufficient exercise or the like and highly correlated with obesity, hypertension, abnormality in the metabolism of sugar or lipid or the like, life style guidance plays an important role as non-drug therapy in order to correct the life style. In particular, dietary therapy to avoid excessive intake of purine has a major rule. However, it is difficult to continue such diet therapy and improvement of the life style, and they often fail.
An agent to regulate the digestion and absorption of purine which is different from existing agents such as a uric acid synthesis inhibitor or a uricosuric drug has been suggested for use as a part of or instead of dietary therapy (for example, see the Japanese patent publication no. 2001-163788). The invention described in the patent publication relates to a drug to regulate the digestion and absorption of purine including chitosan for human, and the dosage is within the range of 2 to 2000 mg/kg/day which is rather high. In addition, it is used in the form of drink or food, and thus mainly used as an supplement in the dietary therapy. Moreover, an agent and food for the improvement of hyperuricemia including chitosan or dietary fiber as an active ingredient other than the invention described in the above patent publication have been developed (for example, see the Japanese patent no. 2632577). Although the effects of chitosan or dietary fiber described in these gazettes are not clear, it is suspected that purine binds to or is trapped by a polymer, chitosan or dietary fiber, and so the production of uric acid decreases.
On the digestion and absorption pathway of nucleic acid in human, nucleic acids are released in the intestine from a nucleic acid and nucleoproteins ingested, and these nucleic acids are broken down into mononucleotides by ribonucleases, deoxyribonucleases and polynucleotidases. Furthermore, it is considered that the pathway wherein mononucleotide is degraded into nucleoside by nucleotidases and phosphatase and then the nucleosides are absorbed is the main pathway. In the pathway, it is considered that the absorbed purine nucleoside is changed to uric acid (for example, see Harper's Biochemistry, translation of the original edition 25, p. 417, 2001). As other pathways, it can be suspected that purine nucleoside is broken down to form purine base and then absorbed, or purine base contained in food is directly absorbed. However, these pathways have not been yet unexplained in detail.
Membrane proteins called nucleoside transporter relate to the nucleoside uptake in the intestine. As such transporters, there are Equilibrative transporters which have transport process of nucleoside into the cell by the concentration gradient of nucleoside (hereinafter referred to as ENT) and sodium-dependent nucleoside transporters which are driven by the concentration gradient of ion between in and out of the cell (hereinafter referred to as CNT) in mammalian cells (for example, see Membrane Transporters as Drug Targets, pp. 318-321, 1999). As human nucleoside transporters, two types of ENT, Type 1 (hereinafter referred to as ENT1) and Type 2 (hereinafter referred to as ENT2), have been identified and cloned so far (for example, see NATURE MEDICINE, Vol. 3, No. 1, pp. 89-93, 1997; and The Journal of Biological Chemistry, Vol. 273, No. 9, pp. 5288-5293, 1998). In addition, three types of CNT, Type 1 (hereinafter referred to as CNT1), Type 2 (hereinafter referred to as CNT2) and Type 3 (hereinafter referred to as CNT3) have been identified and cloned (for example, see American Journal of Physiology Cell Physiology, Vol. 272, pp. C707-C714, 1997; American Journal of Physiology Renal Physiology, Vol. 273, pp. F1058-F1065, 1997; The Journal of Biological Chemistry, Vol. 276, No. 4, pp. 2914-2927, 2001).
The distribution and characteristics of these transporters have been confirmed to some extent. Regarding ENTs, both ENT1 and ENT2 exist broadly in human normal tissues and transport both purine and pyrimidine nucleosides. In terms of function, their sensitivities to the inhibition by nitrobenzylthioinosine (hereinafter referred to as NBMPR) are different, that is, ENT1 is markedly inhibited by a low concentration of NBMPR (IC50<5 nM), while ENT2 is hardly inhibited by NBMPR, but is inhibited only by a high concentration of NBMPR (IC50>1 μM) (for example, see Membrane Transporters as Drug Targets, pp. 316-318, 1999).
On the other hand, regarding CNTs, CNT1 transports pyrimidine nucleoside and adenosine, and the messenger RNA (hereinafter referred to as mRNA) has been confirmed to exist in the jejunum and kidney in rats. CNT2 transports purine nucleoside and uridine, and various kinds of mRNA have been confirmed to exist in organs including the heart, liver, skeletal muscles, kidney, intestines or the like in human. CNT3 has been recently cloned and transports both purine and pyrimidine nucleosides, and the mRNA has been confirmed to exist in the bone marrow, pancreas, intestines and mammary gland in human. In addition, in terms of function, it has been confirmed that all of these CNTs are not influenced by NBMPR (for example, see The Journal of Biological Chemistry, Vol. 276, No. 4, pp. 2914-2927, 2001; and Membrane Transporters as Drug Targets, pp. 327-332, 1999).
In addition, in the previous studies on transport mechanism in the intestines, it is shown that nucleoside is taken up through CNT from mucosal side and transported through ENT from serosal side (for example, see Gastrointestinal transport, molecular physiology, pp. 334-337, 2001). However, the contribution of nucleoside transporters in the human intestines, especially in the human small intestine has been not clarified in detail.
On the other hand, in the gazettes of Japanese patent publication no. 2001-163788 and Japanese patent no. 2632577, it has been reported that plasma uric acid level is lowered by inhibiting purine absorption. Additionally, it was confirmed that plasma uric acid level is lowered by restriction on eating dietary sources of purine in human, and that uric acid synthesized from purine nucleosides absorbed in the intestine reflects plasma uric acid concentration (for example, see Proceedings of the Nutrition Society, Vol. 41, pp. 329-342, 1982) Therefore, plasma uric acid level can be controlled by effective inhibition of the purine nucleoside absorption through the intestines.
Some compounds including dipyridamole have been reported so far as an inhibitor of a nucleoside transporter (for example, see Japanese patent publication no. H6-247942, Japanese patent publication no. Tokuhyo 2002-504134, and Japanese patent publication no. Tokuhyo 2001-517226). All of these inhibitors are ENT inhibitors, and mainly used as a drug for the cardioprotection, treatment of pain, enhancement of antitumor drug or the like. On the other hand, there has not been any report on a CNT inhibitor so far. Moreover, it has not ever been reported or suggested that a compound having an inhibitory activity on CNT2 can inhibit the purine nucleoside absorption through the intestines effectively, and is useful as a drug for a disease associated with an abnormality of plasma uric acid level.
In addition, it was reported that as a glycosylated benzimidazole derivative, a benzimidazole derivative glycosylated with L-ribose is useful for the prevention or treatment of virus infection such as herpes virus or coronary restenosis. However, any benzimidazole derivative glycosylated with D-ribose has not been reported. Furthermore, it has not ever been reported or suggested that a glycosylated benzimidazole derivative is useful for the prevention or treatment of a disease associated with an abnormality of plasma uric acid level such as gout, hyperuricemia or the like (see International publication no. WO97/25337 pamphlet, U.S. Pat. No. 6,204,249 gazette, U.S. Pat. No. 6,617,315 gazette or the like).